Does Cholesterol Cause Coronary Artery Disease ?

In the Sept 2018 Amer J Med, Dr Robert Dubroff points out an inconvenient truth. Since clinical trial regulations were tightened in 2004, there have been 29 major randomized controlled trials of cholesterol reduction. (1) Only 2 of 29 show a mortality benefit, and 66% of the studies show no cardiovascular benefit at all. (1) Dr Dubroff says:

“only 2 of these 29 studies reported a mortality benefit, while nearly two-thirds reported no cardiovascular benefit at all. These unfavorable outcomes and inconsistent results suggest that the lipid hypothesis has failed the test of time….Three decades of RCTs (randomized controlled trials), however, have yielded inconsistent and contradictory results. We must acknowledge these anomalies and either modify or reject the lipid hypothesis….the pathogenesis of atherosclerosis is far more complex than originally thought.“(1) End quote

The randomized controlled trial (RCT) is the gold standard for validating or rejecting a medical hypothesis. Initial proof of the lipid hypothesis came from some of the earliest RCTs of cholesterol reduction, such as the Coronary Primary Prevention Trial of cholestyramine and the first statin trials (Scandinavian Simvastatin Survival Study [4S], West of Scotland Coronary Prevention Study [WOSCOPS], and Cholesterol and Recurrent Events [CARE]).

More widespread trials over the next 20 years produced mixed results, however.2 Regrettably, some clinical trials prior to 2004 have been tainted by scandals that led to new clinical trial regulations intended to safeguard patients and lend credibility to subsequent trials.3, 4 The table summarizes 29 major RCTs of cholesterol reduction reported after the publication of these regulations (Table). Notably, only 2 of these 29 studies reported a mortality benefit, while nearly two-thirds reported no cardiovascular benefit at all.These unfavorable outcomes and inconsistent results suggest that the lipid hypothesis has failed the test of time. Alternatively, some have suggested that this lack of benefit could be due to inadequate intensity or duration of treatment, insufficiently powered studies, targeting LDL-C instead of apolipoprotein B, or perhaps these trials are attempting to lower LDL-C too late in the course of the disease.

Final Thoughts: LDL-C is considered the primary constituent of atherosclerotic plaque. Therefore, it stands to reason that lowering serum LDL-C should prevent cardiovascular disease. Three decades of RCTs, however, have yielded inconsistent and contradictory results. We must acknowledge these anomalies and either modify or reject the lipid hypothesis. Clearly, some individuals do benefit from lipid-modifying therapy. I believe the real question is how to identify them. Our current approach of focusing almost exclusively on lowering LDL-C for everyone does not consistently work, may result in unnecessary treatment of some healthy individuals, and likely reflects the fact that the pathogenesis of atherosclerosis is far more complex than originally thought. Our LDL-C-centric approach to cardiovascular disease prevention may have distracted us from investigating other pathophysiologic mechanisms and treatments. Last, we should not ignore the benefits of a healthy lifestyle. Although changing our patients’ lifestyle is more difficult than prescribing a pill, the benefits are far more robust.22

The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease. This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point. Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information.

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